A practical synthetic method for vinyl chlorides and vinyl bromides from ketones via the corresponding vinyl phosphate intermediates

Article abstract of DOI:10.1016/j.tetlet.2004.11.075

A new synthetic method for the preparation of vinyl chlorides and vinyl bromides from acyclic and cyclic ketones is described. Vinyl halides are practically obtained from the corresponding vinyl phosphate intermediates with triphenylphosphine dihalide.

Full text of DOI:10.1016/j.tetlet.2004.11.075

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 229–232
A practical synthetic method for vinyl chlorides and
vinyl bromides from ketones via the corresponding
vinyl phosphate intermediates
Katsuhide Kamei,a,* Noriko Maedaa and Toshio Tatsuokab
aDaiichi Suntory Biomedical Research Co., Ltd, 1-1-1, Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618-8513, Japan
bDaiichi Suntory Pharma Co., Ltd, Mori Bldg. No. 31, 5-7-2, Kojimachi, Chiyoda-ku, Tokyo 102-8530, Japan
Received 21 October 2004; revised 11 November 2004; accepted 12 November 2004
Abstract—A new synthetic method for the preparation of vinyl chlorides and vinyl bromides from acyclic and cyclic ketones is
described. Vinyl halides are practically obtained from the corresponding vinyl phosphate intermediates with triphenylphosphine
dihalide.
Ó 2004 Elsevier Ltd. All rights reserved.
Vinyl halides have become important intermediates in
organic synthesis for C–C and C–N bond formation
such as Pd-catalyzed coupling reaction1 and vinyl radi-
cal cyclization.2 Recently, we have reported SUN
N4057, which has a vinyl chloride moiety, as a pharma-
ceutical candidate for the treatment of acute phase of
cerebral infarction (Figure 1).3 In this research project,
we need to develop a practical synthetic method for
vinyl halides. Although vinyl halides in general are pre-
pared from alkynes4 and/or aldehydes,5 these methods
are restricted to the application of simple substrates such
as terminal vinyl halides. Vinyl halides can also be syn-
thesized from ketones by using acetyl halide in a strong
acid solvent,6 thionyl chloride,7 phosphorus trihalide,8
phosphorus pentahalide,9 phosphorus oxyhalide,3,10
and so on.11,12 However these methods suffer from dis-
advantages such as usage of a large amount of acid
halide, low yields in some cases, contamination of insep-
arable gem-halide compounds11 and/or various other
by-products.8,12,13 To make matters worse, at the
work-up procedure there are risks of generating acid
gas, a sudden rise in temperature and a bumping in
the neutralization reaction for treatment and decompo-
sition of the excessive acid halide and, therefore, these
method are unsuitable for the industrial scale of
application.
In this letter, we present a facile preparation of vinyl
halides 3 from ketones 1 via the corresponding vinyl
phosphate intermediates 2 with triphenylphosphine
dichloride and triphenylphosphine dibromide (Scheme
1).
Triphenylphosphine dichloride (Ph3PÆCl2) and triphen-
ylphosphine dibromide (Ph3PÆBr2) were used as
obtained from commercial sources. Vinyl phosphates 2
were obtained from ketones 1 in reasonable yields (67–
100%) according to the procedure similar to that
described in the literatures.14 Vinyl phosphate 2 was
treated with 1.2 equiv of fresh Ph3PÆCl2 or Ph3PÆBr2 in
acetonitrile at room temperature, giving the correspond-
ing vinyl halide 3 in 2 h.15 As shown in Table 1, chlori-
nation and bromination of vinyl phosphates 2 with
Ph3PÆCl2 and Ph3PÆBr2 proceeded smoothly in suitable
yields (54–91%). Not only acyclic ketone 1a but also cyc-
lic ketones 1b, 1c were converted to vinyl halide deriva-
tives (entries 1–6). We have found that this method was
O
N
N
N
Cl
2 HCl
O
Figure 1. Structure of SUN N4057.
Keywords: Vinyl chlorides; Vinyl bromides; Ketones; Vinyl phos-
phates; Triphenylphosphine dihalides; SUN N4057.
*
Corresponding author. Tel.: +81 75 962 8194; fax: +81 75 962 6448;
e-mail: katsuhide_kamei@dsup.co.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.075

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K. Kamei et al. / Tetrahedron Letters 46 (2005) 229–232
.
R1
X
PPh3 X2
ClP(O)(OEt)2
R1
OP(O)(OEt)2
R1
R2
O
CH3CN, r.t.
KHMDS
THF
R2
3
R2
2
1
(X = Cl, Br)
Scheme 1. Preparation of vinyl halides 3 from ketones 1 via the corresponding vinyl phosphates 2.
Table 1. Chlorination and bromination of vinyl phosphate 2
Entry
1
Ketone 1
Vinyl phosphate 2
Reagent
Vinyl halide 3
% Yield from 2
PPh3ÆCl2
70
Ph
O
Ph
OP(O)(OEt)2
Ph
Cl
1a
2a
4
5
CH3
CH2
CH2
Br
CH2
Cl
Ph
2
3
1a
2a
PPh3ÆBr2
PPh3ÆCl2
69
83
O
OP(O)(OEt)2
1b
2b
6
7
Br
4
5
6
7
8
1b
2b
PPh3ÆBr2
PPh3ÆCl2
PPh3ÆBr2
PPh3ÆCl2
PPh3ÆBr2
54
61
64
91
87
O
OP(O)(OEt)2
O
Cl
1c
2c
8
Cl
Cl
Cl
Cl
O
O
Br
1c
2c
9
O
O
O
O
CH3
O
CH3
CH3
N
N
N
1d
2d
10
11
OP(O)(OEt)2
Cl
O
O
O
O
CH3
Br
N
1d
2d
O
Cl
Cl
applicable to the imide 1d as well, giving vinyl halides in
high yields (entry 7, 8). By the same procedure the vinyl
chloride 14, the intermediate compound for SUN
N4057, was synthesized from imide 123 via the corre-
sponding vinyl phosphate 13 in good yield (Scheme 2).
In all cases, no by-product was observed and the
work-up process was easy and safe (see a typical
procedure15).
O
N
O
ClP(O)(OEt)2
N
KHMDS, -78oC
THF (92%)
O
OP(O)(OEt)2
O
O
12
13
Cl
O
.
N
PPh3 Cl2
Although a reaction of b-diketones with triphenylphos-
phine dihalides has been reported,16 in which conjugate
addition of halide ion to b-triphenylphosphoniumoxy
a,b-unsaturated ketones afford b-halo a,b-unsaturated
ketones, monocarbonyl compound did not directly react
with triphenylphosphine dihalides. In our new method,
once a monocarbonyl compound 1 is converted to the
corresponding vinyl phosphate intermediate 2, it may
be easily transformed into vinyl halide 3.17
SUN N4057
Cl
CH3CN, r.t.
(99%)
O
14
Scheme 2. Application to the intermediate 12 of SUN N4057.
ated by X2 (X = Cl, Br), giving an oxonium-triphenyl-
phosphonium derivative 15. A halide ion consecutively
attacks carbonyl moiety to form a carbon–halide bond.
Intramolecular transfer and elimination reaction of 16
A tentative reaction mechanism is as follows (Scheme 3).
A vinyl phosphate intermediate 2 reacts with PPh3 activ-

K. Kamei et al. / Tetrahedron Letters 46 (2005) 229–232
231
Ph
O
X-
Ph P+
Ph
X
OEt
OEt
R1
R2
OP(O)(OEt)2
R1
R2
O+ P
X-
X-
P+ Ph
Ph Ph
(X = Cl, Br)
15
2
OEt
OEt
X
R1
R2
X
R1
R2
O P OEt
O
O P OEt
O
X-
X-
+
P+ Ph
P+ Ph
Ph Ph
Ph Ph
(X = Cl, Br)
3
16
Aqueous work up
PPh3=O, P(O)(OH)(OEt)2, HX
Scheme 3. A tentative reaction mechanism.
3. Kamei, K.; Maeda, N.; Ogino, R.; Koyama, M.; Naka-
jima, M.; Tatsuoka, T.; Ohno, T.; Inoue, T. Bioorg. Med.
Chem. Lett. 2001, 11, 595–598.
smoothly occurs to generate the vinyl halide 3 and
PPh3@O.
4. (a) Brown, H. C.; Subrahmanyam, C.; Hamaoka, T.;
Ravindran, N.; Bowman, D. H.; Misumi, S.; Unni, M. K.;
Somayaji, V.; Bhat, N. G. J. Org. Chem. 1989, 54, 6068–
6075; (b) Pattenden, G.; Plowright, A. T.; Tornos, J. A.;
Ye, T. Tetrahedron Lett. 1998, 39, 6099–6102.
In summary, we described a new practical synthetic
method for the preparation of vinyl chlorides and vinyl
bromides from acyclic ketones as well as cyclic ketones
via the corresponding vinyl phosphate intermediates.
This new process is satisfactory in an industrial scale
of production since the work-up procedure is easy to
operate. Moreover, this method is applicable to imide
carbonyl moiety, and now we have applied to the indus-
trial production of SUN N4057. The reaction mecha-
nism in detail and applications to more versatile
substrates are currently under investigation.
´
´
5. (a) Martınez, A. G.; Alvarez, R. M.; Gonzalez, S. M.;
Subramanian, L. R.; Conrad, M. Tetrahedron Lett. 1992,
33, 2043–2044; (b) Takai, K.; Nitta, K.; Utimoto, K.
J. Am. Chem. Soc. 1986, 108, 5065.
6. Moughamir, K.; Mezgueldi, B.; Atmani, A.; Mestdagh,
H.; Rolando, C. Tetrahedron Lett. 1998, 39, 59–62.
7. Burkhard, J.; Janku, J.; Vodicka, L. Coll. Czech. Chem.
Commun. 1988, 53, 110–113.
´ ´
8. Eszenyi, Y.; Tımar, T.; Sebo¨k, P. Tetrahedron Lett. 1991,
32, 827–828.
9. Fry, A. J.; Moore, R. H. J. Org. Chem. 1968, 33, 425–426.
10. Hurd, C. D.; Hayao, S. J. Am. Chem. Soc. 1954, 5065.
11. Horner, V. L.; Oediger, H.; Hoffmann, H. Justus Liebigs
Ann. Chem. 1959, 626, 26–34.
12. Isaacs, N. S.; Kirkpatrick, D. J. Chem. Soc., Chem.
Commun. 1972, 443–444.
13. Jacobs, T. L. Org. React. 1949, 5, 20–23.
Acknowledgements
We wish to thank Dr. H. Annoura and Dr. A. Mizuno
for their encouragement throughout this work. We
are grateful to Mr. T. Fujita, Suntory Institute for
Bioorganic Research, for the measurement of HRMS.
14. Calogeropoulou, T.; Hammond, G. B.; Wiemer, D. F.
J. Org. Chem. 1987, 52, 4185–4190.
Supplementary data
15. A typical procedure is as follows: to a stirred solution of
4-methyl-1,4-benzoxazepin-5(4H)-one-3-yl diethyl phos-
phate 2d (176 mg, 0.54 mmol) in 4 mL of anhydrous
acetonitrile was added triphenylphosphine dichloride
(214 mg, 0.65 mmol) at room temperature under argon
atmosphere, and then stirring was continued for 2 h. The
reaction mixture was diluted with EtOAc (20 mL) and
washed with a saturated solution of NaHCO3 and brine.
After drying over MgSO4, removal of the solvent in vacuo
gave a residue, which was chromatographed over SiO2
using n-hexane/EtOAc (6:1) as an eluent to give the vinyl
chloride 10 (103 mg, 91%). Colorless oil; 1H NMR
(CDCl3)d 3.30 (s, 3H), 6.65 (s, 1H), 7.02 (d, 1H,
J = 8 Hz), 7.24 (t, 1H, J = 8 Hz), 7.45 (t, 1H, J = 8 Hz),
7.91 (d, 1H, J = 8 Hz); IR (CHCl3) cmÀ1: 1657, 1605,
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.11.075.
References and notes
1. (a) Heck, R. F. Palladium Reagents in Organic Synthesis;
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Academic: London, 1985; (b) Barluenga, J.; Fernandez,
M. A.; Aznar, F.; Valdes, C. Chem. Commun. 2002, 43,
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2. (a) Ramaiah, M. Tetrahedron 1987, 43, 3541–3676; (b)
Nugent, B. M.; Williams, A. L.; Prabhakaran, E. N.;
Johnston, J. N. Tetrahedron 2003, 59, 8877–8888.

232
K. Kamei et al. / Tetrahedron Letters 46 (2005) 229–232
1454, 1358, 1339; FABMS m/z: 210 [MH]+; HRMS: calcd
for C10H9ClNO2 210.0322 [MH]+. Found 210.0316.
16. (a) Piers, E.; Nagakura, I. Synth. Commun. 1975, 5, 193–
199; (b) Piers, E.; Grierson, J. R.; Lau, C. K.; Nagakura, I.
Can. J. Chem. 1982, 60, 210–223.
17. In Ref. 11, a reaction of cyclohexanone with Ph3PÆCl2 has
been described. Although we took a makeup, 1-chloro-
cyclohexene was not generated at all. It was also found
that all substrates 1a–d, 12 were unreactive with Ph3PÆCl2
directly.